Chromatin modifications are likely to be key in long-lasting adaptive and maladaptive changes induced by drugs of abuse. Sensitization to the locomotor effects of cocaine following repeated administration is an established animal model of long-lasting functional changes induced by this psychostimulant. We have observed that a high dietary intake of free methionine leads to increased locomotor responses to cocaine without affecting the level of cocaine-induced dopamine efflux in the nucleus accumbens, as measured by microdialysis. Methionine treatment was found in the 1960s to exacerbate symptoms in patients with schizophrenia, a disease characterized by dopaminergic overactivation. Increased expression of DNA methyl transferase 1 (DNMT1) was also observed in schizophrenia and exogenous administration of high doses of methionine to animals is considered to be an animal model of this disease. Together, these results suggest the hypothesis that DNA hypermethylation induced by high dietary methionine of a subset of genes may be critically important in regulating locomotor responses to cocaine by increasing sensitivity to dopaminergic neurotransmission in target regions like the nucleus accumbens. To test this hypothesis, Specific Aim 1 of the present exploratory application will be aimed at identifying cocaine responsive genes differentially regulated by dietary methionine levels. To this aim we will use high-density microarrays (Affymetrix) in microdissected nucleus accumbens samples to identify genes that are regulated by chronic cocaine and dietary methionine. As a second level of analysis, a systems biology strategy will be used to deconvolve the transcriptional network in order to identify specific gene modules and gene regulatory hubs involved in sensitization to the locomotor effects of cocaine. Changes in DNA methylation in the promoter regions of candidate genes identified by microarray analyses will also be investigated. Specific Aim 2 will investigate the effect of high free dietary methionine on cocaine-induced conditioned place preference (CPP) in order to determine whether dietary methionine also affects cocaine's rewarding properties. The proposed project is aimed at identifying genes regulated by dietary methionine that contribute to cocaine-induced long-lasting effects. Since altered DNA methylation has also been implicated in schizophrenia and since a substantial proportion of cocaine users experience psychosis, the results of the present study may also indicate novel genes that have significant roles in primary psychotic disorders, such as schizophrenia and bipolar disease.